Plexiform Neurofibroma Research Articles

TMOD-26. GENERATION OF A CHROMOSOME 8 GAIN;NF1-/- HIPSC-DERIVED SCHWANN CELL PRECURSOR MODEL

Abstract Neurofibromatosis type 1 (NF1) is an autosomal dominant cancer predisposition syndrome caused by a germline mutation in the NF1 gene. The loss of the second copy of NF1 within Schwann cell precursors (SCPs) contributes to the formation of plexiform neurofibromas (PNs) found in 30-50% of NF1 patients. PNs can progress into malignant peripheral sheath tumors (MPNSTs), an aggressive form of cancer and a leading cause of mortality in NF1 patients. Our lab previously demonstrated frequent chromosome 8 (Chr8) gain in NF1-MPNST patient-derived xenografts (PDX) and patient tumors. To investigate Chr8 gain’s role, we created isogenic NF1-/- iPSC cell lines with and without Chr8 gain. Trisomy 8 fibroblasts were obtained and single-cell cloned to establish wildtype (WT) and Chr8 gain populations. Washington University’s Genome Engineering & Stem Cell Center (GESC@MGI) reprogrammed these cells into human induced pluripotent stem cells (hiPSCs). Using synthetic gRNA and CRISPR/Cas9, NF1 knockout lines were generated. Four iPSC cell lines were differentiated into SCPs, and cell survival and proliferation were assessed using Incucyte cell survival and CellTiter-Glo® Assay. Fluorescence in situ hybridization (FISH) and karyotyping validated the human iPSCs. qPCR revealed high expression of iPSC markers OCT3/4 and SOX2 in all iPSC lines. After differentiation, SCP markers (GAP43 and ITGA4) were upregulated in WT, NF1-/-, and Chr8 gain;NF1-/- SCP lines, demonstrating successful differentiation. Furthermore, Chr8 gain; NF1-/- SCPs displayed enhanced proliferation and increased cell survival compared to WT and NF1-/- SCPs, suggesting improved characteristics in the presence of Chr8 gain. In summary, our research provides insights into Chr8 gain and NF1 loss effects on SCP differentiation, proliferation, and survival. Understanding these molecular mechanisms may contribute to developing targeted therapies for NF1.

INNV-13. OPHTHALMOLOGICAL COMPLICATIONS IN NF-1 PATIENTS RECEIVING MEK INHIBITORS: MD ANDERSON CANCER CENTER EXPERIENCE

Abstract BACKGROUND MEK inhibitors (MEKi) are a novel therapy for plexiform neurofibromas and optic gliomas in Neurofibromatosis type 1 (NF1). Potential ophthalmic complications are MEKi-induced retinopathy (MEKAR) requiring regular ophthalmologic assessments. We assess the importance of screening and ocular adverse events (OAE) in pediatric NF1 patients receiving MEKi. METHODS We reviewed 45 NF1 patients with baseline and follow-up examinations before and post MEKi treatment initiation. Evaluations included comprehensive eye examination, visual acuity, dilated fundoscopic examination, optical coherence tomography (OCT) of the macula and nerve fiber layer, and Humphrey visual field testing. RESULTS Twenty-six (62% male) of 45 patients were included. Median age at treatment was 15 (range 2-23) years. Plexiform neurofibromas were the most common indication for MEKi (n=22). Selumetinib was the most common MEKi (n=19, 77%), then trametinib (n=6, 23%), and mirdametinib (n=1, 4%). Only two patients had to switch to different MEKi. Patients were followed for a mean of 413-days after treatment initiation (range 103-1122 days) for an average of 3.85 ophthalmology exams per patient. No retinopathy was observed at each of the 3–6 month follow-ups. Around 15% of patients experienced dry eye symptoms with none requiring artificial tears for management. Seven patients had pre-existing optic neuropathy. No dose adjustments were needed due to OAEs. One patient’s visual acuity decreased temporarily but returned to baseline and the patient remains on MEKi. CONCLUSIONS Regular ophthalmologic assessments are crucial for NF1 patients undergoing MEKi treatment. Consensus guidelines on frequency of ophthalmologic screening during MEKi treatment are not well reported. In our cohort no patients had MEKAR at regular 3–6 month follow ups. In addition to baseline screening, future larger cohort studies are needed to confirm if decreasing the frequency of retinal exams is safe while on MEKi to inform future clinical screening guidelines for NF1 patients on MEKi.

CNSC-07. OLIGODENDROGLIAL IMPAIRMENT IN WHITE MATTER TRACTS FOLLOWING NEUROFIBROMATOSIS TYPE 1 (NF1) GERMLINE MUTATION OR CARBOPLATIN TREATMENT

Abstract Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome due to mutations in the NF1 gene. The disease affects 1 in 2500-3000 people worldwide and patients are predisposed to neoplasms such as optic pathway glioma, plexiform neurofibroma. In addition, NF1 patients often experience neurological issues such as learning difficulties. Unfortunately, there is no cure for NF1 yet. Chemotherapy (e.g., carboplatin) remains the first-line treatment for NF1-associated low-grade glioma; while effective in reducing tumor burden, it does not reliably restore neuronal function. In this study, we sought to determine how chemotherapy and Nf1 germline mutations influence neurological function, using genetically engineered mice of NF1. Nf1-heterozygous mice received carboplatin (60 mg/kg/day) or vehicle every other day for one week. Their optic nerves were collected and processed for immunofluorescence and transmission electron microscopy (EM). We found that carboplatin treatment reduces the density of oligodendrocytes in Nf1-heterozygous mice and impairs myelination. Moreover, a similar effect of carboplatin was observed in wild-type mice, suggesting that carboplatin impairs oligodendroglia independent of the NF1 status and the effect of carboplatin should also be evaluated in the non-NF1 context. In another set of experiments, we sought to understand how germline Nf1 mutations influences oligodendroglia. Whereas we did not observe a difference in optic nerve oligodendrocyte density in mice with an engineered mutation targeting the GTPase-activating protein-related domain (GRD) domain of the Nf1 gene, a reduction of oligodendrocyte density was observed in mice harboring a patient-derived mutation (R1809C), which localizes outside of the GRD. A similar effect was observed in the corpus callosum of Nf1+/R1809C mice together with myelin impairment, suggesting a RAS-independent mechanism of Nf1 regulation of oligodendrocytes. Together, these findings indicate that both Nf1 germline mutations and chemotherapy could contribute to oligodendrocyte and myelin deficits in white matter tracts.

INNV-12. CUTANEOUS TOXICITIES OF MITOGEN-ACTIVATED PROTEIN KINASE INHIBITORS IN CHILDREN AND YOUNG ADULTS WITH NEUROFIBROMATOSIS-1

Abstract BACKGROUND Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder which commonly causes neoplasms leading to disfigurement or dysfunction. Mitogen-activated protein kinase inhibitors (MEKi) are generally well-tolerated treatments which target neural tumor progression in patients with NF1. Cutaneous adverse events (CAEs) are common and may hinder patients’ abilities to remain on treatment, particularly in children. We aim to characterize CAEs secondary to MEKi treatment in pediatric and young adult patients with NF1. METHODS We reviewed institutional medical records of patients under 30 years with a diagnosis of “NF1,” “NF2,” or “other neurofibromatoses” on MEKi therapy between January 1, 2019 and June 1, 2022. We recorded the time-to-onset, type, and distribution of CAEs, non-cutaneous adverse events (AEs), AE management, and tumor response. RESULTS The median age of 40 patients with NF1 was 14 years old. Tumor types included low-grade gliomas (51%) and plexiform neurofibromas (38%). MEKi used included selumetinib (69%), trametinib (25%), and mirdametinib (6%) (Table 1). A total of 74 CAEs occurred, with 28 cases of acneiform rash (38%) (Figure 1). Twenty-three out of the 28 cases of acneiform eruption were in post-pubertal patients (82.1%). Other common CAEs were paronychia, seborrheic dermatitis, eczema, xerosis, and oral mucositis. The most common treatments included oral antibiotics and topical corticosteroids. Most patients had clinical (stable or improved) tumor response (71%) while 29% had tumor progression while on a MEKi (Table 2). There was no significant association between CAE presence and tumor response (p=0.39). CONCLUSIONS MEK inhibitors have been demonstrated as a valuable treatment, but CAEs complicate the ability to stay on the treatment. Most patients in our cohort developed a CAE, demonstrating its prevalence in this population. Improvement in characterization of MEKi toxicities and their management is important to develop treatment guidelines for pediatric and young adult patients with NF1 on MEKi therapy.

EXTH-62. FOCAL ADHESION KINASE (FAK) IN CHROMOSOME 8 GAIN-ASSOCIATED MALIGNANT PERIPHERAL NERVE SHEATH TUMORS (MPNST)

Abstract OBJECTIVES Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas often associated with Neurofibromatosis type 1 (NF1), a genetic syndrome driven by overactivation of the RAS pathway. MEK inhibitors (MEKi) target downstream components of the RAS pathway and have been approved for NF1 patients with plexiform neurofibromas (PN). However, MPNST often develop resistance to MEKi. Our lab recently discovered the critical role of chromosome 8 (Chr8) genes in MPNST. The Chr8 gene, protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK) is overexpressed in multiple cancers, suggesting its importance in tumor progression. In this study, we aim to evaluate FAK as a therapeutic target for MPNST and investigate the FAKi and RAF/MEKi combination. METHODS A CRISPR gRNA screen was used to identify Chr8 genes involved in MPNST survival. The effect of FAK shRNA knockdown and a FAK inhibitor (FAKi), alone or combined with a MEKi, in MPNST cells was assessed using IncuCyte proliferation assays and multiple murine models. RESULTS The CRISPR gRNA screen identified 57 genes on Chr8 important for MPNST cell survival, including PTK2/FAK. Knockdown of FAK by shRNA in MPNST inhibited cell proliferation in vitro and reduced tumorigenesis in vivo. Consistently, the FAKi defactinib significantly inhibited the proliferation of MPNST (IC50-values: 1.72-4.65μM). Moreover, the defactinib/avutometinib combination was synergistic in vitro and the combination of FAKi with RAF/MEKi reduced tumor growth more that either drug alone in Chr8-gain MPNST PDX models. Avutometinib induced compensatory activation of FAK, while defactinib/avutometinib combination decreased phosphorylation of FAK, ERK1/2 and STAT3, and augmented cleavage of Caspase-3 and PARP-1, shown using the WES protein simple system. CONCLUSION These results demonstrate the potential therapeutic efficacy of FAK inhibitors, both alone and in combination with RAF/MEKi, for the treatment of MPNST.

BIOM-37. EXPLORING L-TYPE AMINO ACID TRANSPORTER 1 (LAT1) AS A DIAGNOSTIC MARKER AND THERAPEUTIC TARGET IN MALIGNANT PERIPHERAL NERVE SHEATH TUMORS (MPNST)

Abstract OBJECTIVES Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that frequently arise from benign plexiform neurofibromas (PN). Approximately half of MPNST are associated with Neurofibromatosis type 1 (NF1). Despite partial elucidation of the molecular mechanisms underlying MPNST, diagnosis remains challenging, and prognosis is poor. Previously, we found that MPNST cells have elevated βIII-spectrin, a cytoskeletal protein involved in cell morphology and regulation of transporters, including L-type Amino Acid Transporter 1 (LAT1). LAT1 facilitates transport of large neutral amino acids and is upregulated in other cancer types. Our objective is to investigate LAT1 as a diagnostic marker and therapeutic target for MPNST. METHODS Gene and protein expression were determined by qPCR and WES protein analysis, respectively. The effect of shRNA knockdown of LAT1 in MPNST cells was assessed using IncuCyte proliferation assays as well as multiple mouse models. Tumor uptake of [18F] FDOPA, primarily transported by LAT1, in MPNST PDX tumors was assessed using PET/CT imaging. RESULTS LAT1 was expressed in MPNST (n=14) vs. benign PN tissues (n=6). Additionally, in human and murine MPNST cells, shRNA-mediated knockdown of LAT1 suppressed proliferation of MPNST cells in vitro and tumor growth in vivo. In a subcutaneous tumor growth model, intratumor injection of shLAT1 lentivirus reduced tumor volume to approximately 50% of control. Furthermore, uptake of [18F] FDOPA by LAT1 in MPNST PDX tumors was detected by PET/CT imaging. WU-356 PDX tissues exhibited higher LAT1 expression as well as increased uptake of [18F] FDOPA in tumors. Conversely, PET imaging showed significantly lower uptake of [18F] FDOPA in LAT1 knockdown tumors (p<0.05). CONCLUSIONS These results suggest that LAT1 promotes the growth and survival of MPNST cells. In addition, these findings demonstrate the potential use of LAT1 and the radiotracer [18F] FDOPA as a diagnostic biomarker in the management of MPNST.

CTNI-46. WINDOW-OF-OPPORTUNITY TRIAL OF ULIXERTINIB FOR MAPK-ACTIVATED LOWER GRADE GLIOMAS IN ADULTS

Abstract Overexpression of MAPK (Ras-Raf-MEK-ERK) signaling is well known in NF1-associated tumors. MEK inhibition has shown promising results in pediatrics NF1-associated tumors. In addition, we have observed augmented MAPK signaling and anti-tumor activity with MAPK inhibition in preclinical models of CIC-mutated vs. wild-type oligodendroglioma. Ulixertinib is a small molecule inhibitor of ERK that is being developed as a novel anti-cancer drug. A phase I study of ulixertinib in advanced solid malignancies had shown two central nervous system responses. We hypothesized that ulixertinib crosses the blood-brain barrier (BBB) and it will result in improved responses in MAPK-activated lower-grade gliomas in adults (recurrent NF1-mutated gliomas grade 1,2,3 and oligodendrogliomas grade 2,3 which are enriched in CIC-mutation). This is a window-of-opportunity study of ulixertinib in patients ≥18 yo. Twenty patients who are candidates for non-emergent surgical resection will be enrolled (10 in each cohort). Patients will receive neoadjuvant ulixertinib at 600mg BID. Selected patients will undergo CSF collection 1-week after and all will undergo surgical intervention 2-weeks after initiation of ulixertinib. Patients will then continue treatment until disease progression or unacceptable toxicity. Primary endpoints are ulixertinib tumor concentration and tumor/plasma ratio in enhancing and non-enhancing disease. Secondary endpoints include median PFS, overall response rate (ORR) and disease control rate at 12mo, duration of response, time-to-next intervention and time-to-response, safety profile, and ulixertinib CSF and tumor/CSF ratio. Exploratory endpoint includes ORR of plexiform neurofibromas in NF1 patients. To date, 4 patients have been dosed; 3 CIC-mutated oligodendroglioma and 1 NF1-mutated glioma. A fifth patient with NF1-mutated glioma has been consented. Upon collection of tumor tissue on all 5 patients, initial assessment of tumor and CSF drug concentration will be conducted and presented at the conference. Ulixertinib’s ability to cross the BBB could influence what tumor types may be explored for further patient benefit.

RBIO-07. IMMUNOMODULATORY PATHWAYS MEDIATE RADIOTHERAPY RESPONSE IN MALIGNANT PERIPHERAL NERVE SHEATH TUMORS

Abstract PURPOSE Malignant peripheral nerve sheath tumors (MPNSTs) are the most common cause of death in neurofibromatosis type 1 (NF-1) and are resistant to radiation therapy (RT), yet the mechanisms underlying RT response are poorly understood. Here, we elucidate mechanisms of RT response in NF-1 associated peripheral nerve sheath tumors through genome-wide CRISPRi screens, genomic analysis of mouse models, and molecular analysis of patient-derived tumor specimens. METHODS Patient derived NF1 mutant plexiform neurofibroma (pNF) cells (NF9511b, NF95.6), and MPNST cells (ST88-14; JH2-002) were used to measure RT responses by cell counts and flow cytometry. Genome-wide CRISPRi screens were used to identify functional modifiers of RT response in ST88-14 and JH2-002 MPNST cells. Nf1-/-; Tp53-/- mouse MPNSTs were subcutaneously implanted in immunocompetent C57/B6 mice, irradiated (2Gyx5), and dissociated for single-cell RNA sequencing (scRNA-seq) using 10x Genomics. Human MPNST tumor specimens (n=45) were analyzed with targeted DNA mutation sequencing and methylation arrays for cell type deconvolution. RESULTS Radiation single-dose response curves revealed MPNST cells (IC50 6.85Gy) were radioresistant compared to pNF cells (IC50 3.13Gy). Genome wide CRISPRi screens in ST88-14 and JH2-002 MPNST cells converged on cell cycle, DNA repair, and immunomodulatory gene sets mediating RT sensitivity. Irradiation of subcutaneous mouse Nf1-/-; Tp53-/- MPNSTs significantly decreased tumor growth (p=0.01, t-test). scRNA-seq of 32,763 cells from 4 irradiated and 3 unirradiated mouse Nf1-/-; Tp53-/- MPNSTs identified 8 tumor clusters and 7 non-tumor clusters. Irradiation demonstrated a pro-inflammatory effect with increased T-cell presence (5.8% versus 3.3%, p=0.04, t-test) and greater activation of immunostimulatory genes (Cxcl10, Stat1, Irf7) in T cells. In human MPNSTs, CDKN2A/B deletion (p=0.04, log-rank test) and decreased immune cell composition (p=0.03, log-rank test) were associated with significantly worse overall survival in response to RT. CONCLUSION MPNST RT responses may depend on immunomodulatory mechanisms that could be leveraged to improve clinical RT response.

Transformation sarcomateuse de la tumeur royale chez une patiente atteinte de la maladie de Recklinghaussen à Lomé (Togo)

Introduction: malignant tumors including soft tissue sarcomas can occur during neurofibromatosis type 1. We report a case of sarcomatous degeneration of a plexiform neurofibroma with multivisceral metastases in a Togolese patient with neurofibromatosis type 1. Observation: A 33-year-old female patient with neurofribromatosis type 1 presented with an altered general condition, pain and changes in the appearance of the plexiform tumour of her neurofibromatosis, which had been evolving for one month. Physical examination revealed multiple coffee-white spots (greater than 10), with tumours of soft consistency and variable size, scattered over the body. There was also a larger tumour (approx. 9cmx6 cm), located on the inside of the left ankle, fixed, firm and painful to palpation. The abdomen was enlarged and tender, with no tenderness or contracture. Examination of lymph nodes was normal. Anatomopathological examination of the biopsy-exeresis of this tumour revealed a proliferation of clusters of small, rounded, undifferentiated cells with reduced cytoplasm and hyperchromatic nuclei, with clear anisokaryosis and numerous atypical mitotic figures. There were also a few vascular emboli. We therefore concluded that this plexiform neurofibroma was malignant, and the extension work-up revealed pulmonary, pancreatic and adrenal metastases. The patient died 3 weeks after diagnosis in respiratory distress. Conclusion: Malignant degeneration of plexiform neurofibromas is possible in patients with neurofibromatosis type 1. It is therefore important to monitor these patients for early detection in order to limit the risk of metastasis and death.

ReNeu: A Pivotal, Phase IIb Trial of Mirdametinib in Adults and Children With Symptomatic Neurofibromatosis Type 1-Associated Plexiform Neurofibroma.

Pharmacologic therapies for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PNs) are limited; currently, none are US Food and Drug Administration-approved for adults. ReNeu is an open-label, multicenter, pivotal, phase IIb trial of mirdametinib in 58 adults (≥18 years of age) and 56 children (2 to 17 years of age) with NF1-PN causing significant morbidities. Patients received mirdametinib capsules or tablets for oral suspension (2 mg/m2 twice daily, maximum 4 mg twice daily), regardless of food intake, in 3 weeks on/1 week off 28-day cycles. The primary end point was confirmed objective response rate (ORR; proportion of patients with a ≥20% reduction of target PN volume from baseline on consecutive scans during the 24-cycle treatment phase) assessed by blinded independent central review (BICR) of volumetric magnetic resonance imaging. Twenty-four of 58 adults (41%) and 29 of 56 children (52%) had a BICR-confirmed objective response during the 24-cycle treatment phase; in addition, two adults and one child had confirmed responses during long-term follow-up. Median (range) target PN volumetric best response was -41% (-90 to 13) in adults and -42% (-91 to 48) in children. Both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life (HRQOL) that began early and were sustained during treatment. The most commonly reported treatment-related adverse events were dermatitis acneiform, diarrhea, and nausea in adults and dermatitis acneiform, diarrhea, and paronychia in children. In ReNeu, the largest multicenter NF1-PN trial reported to date, mirdametinib treatment demonstrated significant confirmed ORRs by BICR, deep and durable PN volume reductions, and early, sustained, and clinically meaningful improvement in pain and HRQOL. Mirdametinib was well-tolerated in adults and children.

Cutaneous Toxicities of MEK Inhibitor Use in Children: AComparison of Binimetinib and Selumetinib.

Binimetinib and selumetinib are two mitogen-activated protein kinase kinase (MEK) inhibitors used to treat low-grade gliomas and plexiform neurofibromas. Cutaneous toxicities are commonly associated with MEK inhibitors; however, limited studies have examined cutaneous effects in a pediatric population or whether toxicities vary between MEK inhibitors. We conducted an IRB-approved, single-center, retrospective review of pediatric neuro-oncology patients on binimetinib or selumetinib who presented to NYU from April 2016 through July 2022. Forty-six children met inclusion criteria (23 females, 23 males) with a mean age of 11.7 years. Thirty-three were treated with binimetinib and 13 with selumetinib. Dermatologic adverse events were encountered in 97.8% of the cohort, and the most common were acneiform eruption (63.0%), paronychia (58.7%), and xerosis (54.3%). Children 12 years and older were more likely to have acneiform eruption (p < 0.001) and seborrheic dermatitis (p < 0.001), while children under 12 were more likely to have xerosis (p = 0.037). The incidence of cutaneous adverse events was significantly different between MEK inhibitors for folliculitis and hair pigment dilution (39.4% binimetinib, 0% selumetinib, p = 0.009). Significantly, more patients required MEK inhibitor dose reduction/hold on binimetinib (87.9%) than selumetinib (46.2%) (p = 0.006). Severity of cutaneous disease was not associated with tumor response. Our study confirms dermatologic adverse events are common in children on MEK inhibitors. Age appears to be associated with increased likelihood of certain cutaneous reactions. Overall, the selumetinib patients in our cohort presented with less severe adverse events and decreased risk of MEK inhibitor dose reduction/hold. Our results will aid clinicians in providing appropriate counseling, treatments, and improved preventive care.

Whole-body MRI-based long-term evaluation of pediatric NF1 patients without initial tumor burden with evidence of newly developed peripheral nerve sheath tumors

BackgroundPatients with neurofibromatosis type 1 (NF1) can develop plexiform neurofibromas (PN). Large tumor burden is a predictor for the development of malignant peripheral nerve sheath tumors. Whole-body magnetic resonance imaging (WB-MRI) is the recommended imaging method for the evaluation of PN. WB-MRI is recommended for NF1 patients at transition from adolescence to adulthood. In the absence of internal PN further follow-up WB-MRI is not considered necessary. PN are often detected in early childhood, leading to the assumption that they may be congenital lesions. It remains unclear whether this invariably applies to all patients or whether patients who initially displayed no tumors can still develop PN over time. Therefore, we retrospectively reviewed WB-MRI scans of pediatric patients with NF1 without initial tumor burden and compared these with long-term follow-up scans for presence of newly developed PN.MethodsWe retrospectively reviewed WB-MRI scans of 17 NF1-children (twelve male; median age at initial scan: 9 [IQR 6.1–11.9] years) who initially displayed no PN. MRI scans with a follow-up interval of at least 6 years (median follow-up interval: 9 [IQR 5.6–12.4] years) were reviewed in consensus by two radiologists regarding the development of new PN over time.ResultsNew PN were identified in two out of 17 children without initial tumor burden in follow-up examinations. One of these two patients developed two larger distinct PN of 4.5 cm on the right upper arm and of 2.5 cm on the left thoracic wall between the age of ten and twelve. The second child developed multiple smaller PN along the major peripheral nerves between the age of eleven and 16. In addition, 15 of the children without initial tumor burden did not develop any distinct tumors for a period of at least 6 years.ConclusionOur results indicate that PN can be newly detected in pediatric patients over time, even if no PN were detected on initial MRI scans. Therefore, it seems reasonable to perform at least a second MRI in pediatric NF1 patients at transition to adulthood, even if they did not display any tumor burden on initial MRI, and when the MRI was performed significantly under the age of 18. With this approach, tumors that may have developed between scans can be detected and patients at risk for complications can be identified.

A rare clinical manifestation of plexiform neurofibroma in the absence of neurofibromatosis-1: a case report

Plexiform neurofibroma is a benign tumor of peripheral nerves that occurs in up to 30% of patients with neurofibromatosis type-1 (NF-1). We present a case of a 15-year-old male patient without NF-1, with an 11-year history of a slow growing, painless mass on the left side of the back extending to the gluteal region, with no constitutional symptoms but with some scoliosis. Histology of the mass was compatible with a plexiform neurofibroma. Plexiform neurofibromas commonly occur in, but are not limited to the craniofacial region. The mainstay of treatment is surgical resection, but complete resectability is challenging due to their locally infiltrative growth pattern. This highlights the need for patient-specific management strategies, even when established guidelines are in place.

A single-center case study series assessing the effect of selumetinib use in patients with neurofibromatosis-related plexiform neurofibromas

Abstract Background Neurofibromatosis type 1 (NF1) is a common genetic disorder of phenotypic variability with age-dependent penetrance. This study describes the diagnosis, clinical characterization, management, and outcomes of a large patient cohort with plexiform neurofibroma (PN) treated with selumetinib in a real-world clinical setting. Methods This single-center observational study consecutively enrolled patients with NF1-PN treated with selumetinib from April 2018 to April 2023. Data on clinical features, tumor types and locations, and results from genetic tests were recorded at baseline; details of disease management with selumetinib and surgical intervention and disease evolution including imaging data and evaluations of pain and function were documented. Results Overall, 54 patients with a median age (range) of 16.4 (4.5–58.0) years were enrolled. Most had cutaneous manifestations (88.9%), including cutaneous neurofibromas and PN. Patients underwent [18F]fluorodeoxyglucose (FDG)-PET/CT imaging before treatment to rule out malignant lesions. Initial evaluations included directed MRI, which facilitated future comparisons and allowed for the assessment of PN resectability. Pharmacological treatment with selumetinib (with surgery, without surgery) resulted in the following proportion of patients achieving stable disease (58.8%, 54.3%), partial response (29.4%, 28.6%), and improved pain (58.8%, 37.1%), deformity (17.6%, 20.0%), and functional (17.6%, 20.0%) outcomes, respectively. Conclusions Results from this study demonstrate that NF1-PN can be managed effectively with selumetinib with surgical intervention in some patients. Most patients achieved tumor stability and improved symptom control, and the majority of patients continue under treatment. Effective diagnosis and management were achieved through individualized utility of FDG-PET/CT and MRI imaging and targeted resource allocation.

Stimulator of interferon gene facilitates recruitment of effector CD8 T cells that drive neurofibromatosis type 1 nerve tumor initiation and maintenance.

Plexiform neurofibromas (PNFs) are benign nerve tumors driven by loss of the NF1 tumor suppressor in Schwann cells. PNFs are rich in immune cells, but whether immune cells are necessary for tumorigenesis is unknown. We show that inhibition of stimulator of interferon gene (STING) reduces plasma CXCL10, tumor T cell and dendritic cell (DC) recruitment, and tumor formation. Further, mice lacking XCR-1+ DCs showed reduced tumor-infiltrating T cells and PNF tumors. Antigen-presenting cells from tumor-bearing mice promoted CD8+ T cell proliferation in vitro, and PNF T cells expressed high levels of CCL5, implicating T cell activation. Notably, tumors and nerve-associated macrophages were absent in Rag1-/-; Nf1f/f; DhhCre mice and adoptive transfer of CD8+ T cells from tumor-bearing mice restored PNF initiation. In this setting, PNF shrunk upon subsequent T cell removal. Thus, STING pathway activation contributes to CD8+ T cell-dependent inflammatory responses required for PNF initiation and maintenance.

Parent-child discrepancies in reports of child psychosocial functioning in neurofibromatosis type 1.

Children with neurofibromatosis type 1 (NF1) are at an increased risk for social-emotional difficulties. These difficulties, including depression and anxiety, are typically measured through parental report of child functioning in research and rarely have children with NF1 rated their own well-being. Discrepancies between parent proxy- and child self-report of psychosocial functioning in other populations have been shown to relate to socioemotional problems and distress. This study examined the concordance of parent proxy- and child self-report of child behavioral and social-emotional functioning on selected Behavior Assessment System for Children-Second Edition subscales in families of children with NF1 and plexiform neurofibroma tumors (pNFs). We also sought to explore possible child, family, and community factors relating to discrepancies in reporting for youth with NF1 and pNFs. Overall, parents reported higher symptoms across psychosocial domains (anxiety, depression, and atypicality) in comparison to their children. Furthermore, characteristics like child sex, attention-deficit hyperactivity disorder diagnosis, and family functioning significantly predicted differences in ratings of child functioning. These findings indicate that multi-informant studies are crucial to understanding multiple perspectives among family members in symptom-reporting and risk factors for these discrepancies. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Clinical features and surgical treatments of neurofibromas associated with neurofibromatosis type 1

To explore the clinical features, surgical treatment, and effectiveness of neurofibromas associated with neurofibromatosis type 1 (NF1). A clinical data of 41 patients with NF1 admitted between December 2018 and April 2024 was retrospectively analyzed. There were 15 males and 26 females, with an average age of 27.5 years (range, 5-61 years). Only one type of neurofibroma existed in 3 patients and the rest of the patients had more than two types of neurofibromas. Fourteen patients had total resection of multiple cutaneous neurofibromas (CNF). Eighteen patients of diffuse neurofibromas underwent total, near-total, or subtotal resection. Among the 13 patients of localized nodular neurofibromas, 9 of benign tumors underwent total sub-capsular resection and 4 of malignant peripheral nerve sheath tumor (MPNST) underwent maginal resection, and only 1 underwent postoperative radiotherapy and chemotherapy. Among the 15 patients of plexiform neurofibromas (PNF), 5 patients underwent both superficial and deep PNF resection, 2 underwent the superficial PNF resection, and 8 underwent the large nodular lesions in the deep PNF resection. There were 8 MPNST, of which 7 cases underwent total sub-capsular resection and large tumor capsule resection under neurophysiological monitoring, and 1 case with the tumor located on the top of the head underwent wide resection and skin grafting. One patient underwent proton knife therapy after surgery, 2 patients did not receive radiotherapy, and the remaining patients received conventional radiotherapy. All patients were followed up after surgery, and the follow-up time was 3-66 months, with an average of 25.0 months. Patients with CNF recovered satisfactorily after surgery, and there was no recurrence during follow-up. Patients with diffuse neurofibromas relieved preoperative symptoms after surgery. Three patients with diffuse neurofibromas located in the head and face recurred during follow-up. The patients with benign localized nodular neurofibromas recovered well after surgery, and only 1 patient had transient regional neuralgia after surgery. Among the patients with MPNST, 2 patients died of recurrence and lung metastasis, while the remaining 2 patients had no recurrence and metastasis during follow-up. All preoperative symptoms disappeared in patients with benign PNF, and no tumor recurrence was observed during follow-up. Two patients with PNF located in the brachial plexus had difficulty in shoulder abduction after surgery, 1 patient with PNF located in vagus developed hoarseness after surgery. Among the 8 patients with MPNST in PNF, 1 died of lung metastases and 1 died of systemic failure. The remaining 6 patients were in stable condition during follow-up, and no tumor recurrence or metastasis was observed. According to the clinical features of neurofibromas in patients with NF1, choosing appropriate surgical approaches can obtain good effectiveness. Because of the difficulty of completely resection, diffuse neurofibromas, especially those located in the head and face, are prone to recurrence after surgery. MPNST has the worst prognosis, high incidence of recurrence/metastasis, and short survival period. Total resection combined with radiotherapy can decrease local recurrence.

Expression and its clinical significance of cell-cycle dependent kinase 1 in malignant peripheral nerve sheath tumors

To explore the role and clinical significance of cell-cycle dependent kinase 1 (CDK1) and its upstream and downstream molecules in the development of malignant peripheral nerve sheath tumor (MPNST) through the analysis of clinical tissue samples. A total of 56 tumor samples from MPNST patients ("Tianjin" dataset) who underwent surgical resection, confirmed by histology and pathology between September 2011 and March 2020, along with 17 normal tissue samples, were selected as the research subjects. MPNST-related hub genes were identified through transcriptome sequencing, bioinformatics analysis, immunohistochemistry staining, and survival analysis, and their expression levels and prognostic associations were analyzed. Transcriptome sequencing and bioinformatics analysis revealed that upregulated genes in MPNST were predominantly enriched in cell cycle-related pathways, with CDK1 occupying a central position among all differentially expressed genes. Further differential analysis demonstrated that CDK1 mRNA expression in sarcoma tissues was significantly higher than in normal tissues [based on searching the cancer genome atlas (TCGA) dataset, P<0.05]. In MPNST tissues, CDK1 mRNA expression was not only significantly higher than in normal tissues (based on Tianjin, GSE141438 datasets, P<0.05), but also significantly higher than in neurofibromatosis (NF) and plexiform neurofibromas (PNF) (based on GSE66743 and GSE145064 datasets, P<0.05). Immunohistochemical staining results indicated that the expression rate of CDK1 protein in MPNST tissues was 40.31%. Survival analysis results demonstrated that CDK1 expression was associated with poor prognosis. The survival time of MPNST patients with high CDK1 mRNA expression was significantly lower than that of the low expression group ( P<0.05), and the overall survival trend of patients with positive CDK1 protein expression was worse than that of patients with negative CDK1 expression. Additionally, differential analysis of CDK family genes (CDK1-8) revealed that only CDK1 was significantly upregulated in MPNST, NF, and PNF. Increased expression of CDK1 is associated with poor prognosis in MPNST patients. Compared to other CDK family members, CDK1 exhibits a unique expression pattern, suggesting its potential as a therapeutic target for MPNST.

Clinical experiences in precision treatment of giant plexiform neurofibromas of head, face, and neck

To summarize the treatment strategies and clinical experiences of 5 cases of giant plexiform neurofibromas (PNF) involving the head, face, and neck. Between April 2021 and May 2023, 5 patients with giant PNFs involving the head, face, and neck were treated, including 1 male and 4 females, aged 6-54 years (mean, 22.4 years). All tumors showed progressive enlargement, involving multiple regions such as the maxillofacial area, ear, and neck, significantly impacting facial appearance. Among them, 3 cases involved tumor infiltration into deep tissues, affecting development, while 4 cases were accompanied by hearing loss. Imaging studies revealed that all 5 tumors predominantly exhibited an invasive growth pattern, in which 2 and 1 also presenting superficial and displacing pattern, respectively. The surgical procedure followed a step-by-step precision treatment strategy based on aesthetic units, rather than simply aiming for maximal tumor resection in a single operation. Routine preoperative embolization of the tumor-feeding vessels was performed to reduce bleeding risk, followed by tumor resection combined with reconstructive surgery. All 5 patients underwent 1-3 preoperative embolization procedures, with no intraoperative hemorrhagic complications reported. Four patients required intraoperative blood transfusion. A total of 10 surgical procedures were performed across the 5 patients. One patient experienced early postoperative flap margin necrosis due to ligation for hemostasis; however, the incisions in the remaining patients healed without complications. All patients were followed up for a period ranging from 6 to 36 months, with a mean follow-up duration of 21.6 months. No significant tumor recurrence was observed during the follow-up period. For patients with giant PNF involving the head, face, and neck, precision treatment strategy can effectively control surgical risks and improve the standard of aesthetic reconstruction. This approach enhances overall treatment outcomes by minimizing complications and optimizing functional and cosmetic results.

Emergency management and perioperative strategies for intra-tumoral hemorrhage in neurofibromatosis type 1-related giant plexiform neurofibroma

To review the emergency management and perioperative strategies for ruptured neurofibromatosis type 1 (NF1)-related giant plexiform neurofibroma (PNF), providing a systematic treatment protocol to improve the therapeutic outcomes and quality of life for patients with giant PNF. The literature on the management of giant PNF rupture and hemorrhage was reviewed, and the diagnosis, treatment, and perioperative management were summarized based on clinical experiences. By implementing an integrated diagnostic and treatment strategy that includes early diagnosis, imaging evaluation, emergency ultra-selective arterial embolization combined with surgical excision, acute hemorrhage can be effectively controlled while also reducing the risk of major intraoperative bleeding and minimizing postoperative complications. As a result, this approach significantly improves treatment success rates and patient quality of life. For ruptured NF1-related giant PNF, employing emergency ultra-selective arterial embolization combined with surgical excision, under the collaboration of a multidisciplinary team, can effectively improve treatment success rates, rapidly control bleeding, reduce tumor size, and lower mortality. Future research should focus on assessing the long-term quality of life of patients treated for ruptured and hemorrhaging giant PNF and on further optimizing treatment protocols.